Nitroaromatic-benzalthiosemicarbazones



Patented Sept. 8, 1 953 UNITED STA'FES- PATENT ori-ICE N-IEEBDAROMATIC-BENZALTHIOSEMI- CARBAZON ES Hans Schmidt;Willrpertal-Vohwinkel, and Roberti B'ehnisch, Wuppertal-Elberfeld, Germany, assignorstoyschen'ley Industries, Inc., New York; N1 Y3, a-corporation of, Delaware Nonrawing. Application JulyfillaIflSLiSeriahNoz.

237,836... ImGermany.-:Julyi22;l950

3 Clalms'. (01. 2605 5521.

This invention relatesgcnerally to the.;syn1- thesis .of" organic chemical compounds useful in chemotherapy.-and,"in amore particular sense,.it

comprises certain novel, nuclearly substituted;

benzalthiosemicarbazones having tuberculostatic. properties that make them' useful agents in.

treatment of tuberculosis. These new compounds also are useful in the treatmentofleprosy and other diseases.

In accordance with this invention, it is found that substituted benzalthiosemicarbazones which may be represented by the following formula, are useful chemotherapeuticalagents:

wherein .Ris a .substituent chosen from the group consisting. ofinitro, amino, and acetylamino and Y links the aromatic nuclei a and b, either by a direct .valence. bond. from nuclear. carbon to nuclear carbon, or through a divalent group or radical such as--C(:O);- S-; and -SO2.

It Willi-be obvious, upon-considerationofthe' Example 1 Synthesis of the compound represented by the formula:

About 2.3 grams of 4-nitro-diphenyl-4'-aldehyde are heated to boiling in 100 cc. of alcohol, to which 2 or 3 drops of glacial acetic acid have been added. A hot solution of 1 gram of mml 21' c semicarbazidelm 10 .cc. of. water. is added. to .the. mixture. andithe': resulting solution. is: boiled for azshortperiodof time. The thiosemicarbazone of .4.- -nitro --.diphenyl: 4 aldehyde precipitates from .the reaction mixture-even while. it is still.-

hot. After-cOOIing-and filtering, ZAgrams. of the a desired. thiosemicarbazone; product.. are; ob tained as yellow. crystals, melting at about. 250- CLwithdecomposition. g V V The. same finalproduot. may also be. obtainedv inithefollowing manner; I 7

Approximately 3.3. gramseofi 4=-nitr,o.diphenyl=- a'ealdehydediacetate are-boiled, for 15 minutes. in. 100.. cc. of. alcohol containing 5 cc. .ofeconcentratedahydrochloric; acid After: neutralizing the.

solution by addition of 4.5 grams of sodium ace.- tate, a hot solution of 1 gram of thiosemicarbazide in 10 cc. of water-is-added, then the mixture is. di'llltBiWithlOOrCGaOf water, whichdissolves the precipitated NaCl, and the solution is;

filtered. About 3.1 grams of the final product, melting at about 250 C. with-decomposition, are thus obtained.

The starting material, 4'-nitro-.diphenyl-4'- aldehyde, yellow crystals melting at 127 C., may bee-obtained: byt'conventional methods: of :organic synthesis,.. or.:it maysbezpreparedtfor instance; theareactionxof i lenitroAl-bromomethyle diphenyl; and-f.hexamethylenetetramine .inaan'alcoholic:

- action medium. Thediacetate of 'thealdehyde.

(cry'stalsamelting aat 144?: 0.). is produced :byoxia dizingsr 4 nitro-4-i methyl-diphenyl-vvith' chromic" acid in the presence of acetic anhydride at low temperature.

Example '2 synthesis of the compound represented by the formula:

Approximately 3.6 grams of 4-nitro-benzophenone-4'-aldehyde-diacetate, which may be prepared by oxidation of 4-nitro-4-methyl-benzophenone with chromic acid in a mixture of glacial acetic acid and acetic anhydride to yield crystals melting at 145 C., are heated to boiling in 100 cc. of alcohol containing 5 cc. of hydrochloric acid. After neutralizing the mixture with 4.5 grams of sodium acetate, it is mixed with a hot solution of 1 gram of thiosemicarbazide in 10 cc. of water and the mixture is heated for a brief period of time. After diluting the solution with 100 cc. of water, it is filtered yielding about 3.2 grams of residue, p-nitro-benzophenone-aldehyde-thiosemicarbazone, melting at 232-233 C. with decomposition.

Example 3 Synthesis of the compound represented by the formula and the N-acetyl derivative of this compound.

About 26 grams of l-acetylamino diphenylsulfide-4'-aldehyde, which may be obtained as colorless crystals by reduction of 4-acetylamino- 4'-cyano-diphenylsulfide, using stannous chloride according to the method of Stephen, are boiled for several hours with 12 grams of thicsemicarbazide in a mixture of 250 cc. of alcohol, 25 cc. of water and 2 cc. of glacial acetic acid. The thiosemicarbazone final product begins to precipitate slowly while the mixture is still hot. After cooling, the mixture is filtered and the residue is recrystallized from dilute alcohol. The product which is obtained as colorless crystals, melting at 216 0., yields a dark-green copper complex salt with soluble copper compounds. By saponification of the acetyl group, using an aqueous alcoholic caustic soda solution of strength, the free base, 4-amino-diphenylsulfide- 4'-aldehyde thiosemicarbazone is obtained as colorless crystals which may be recrystallized from alcohol.

Example 4 Synthesis of the compound represented by the formula:

from a. larger quantity of alcohol and have a melting point of 245C. (with decomposition).

Example 5 Synthesis of the compound represented by the formula:

About 3 grams of 4-acetylamino-diphenyl-sulfone-f-aldehyde, which may be obtained as crystals, melting at 204 C. by reacting the potassium salt of 4-acetylamino-benzene-sulfinic acid and 4-chloro-benzaldehyde at C., are boiled with 1.5 grams of thiosemicarbazide for 4 hours in a mixture of 25 cc. of alcohol, 5 cc. of water and 0.5 cc. of glacial acetic acid. The resulting thiosemi- 'carbazone final product, which begins to precipitate while the mixture is still hot, is removed by filtering the mixture, after cooling, and it is recrystallized from alcohol. The final product is obtained as colorless leaflets, melting at C. Having thus described the subject matter of this invention, what it is desired to secure by Letters Patent is:

r l. A compound represented by the formula:

References Cited in the file of this patent FOREIGN PATENTS Number Country Date J. 76,219 Germany 1949 J. 76,679 Germany 1949 OTHER REFERENCES Domagk: Naturwissenschaften, vol. 33, November 30, 1946, p. 315. 

1. A COMPOUND REPRESENTED BY THE FORMULA: 